Sexual Dimorphic Regulation of Body Weight Dynamics and Adipose Tissue Lipolysis

Abstract

BackgroundSuccessful reduction of body weight (BW) is often followed by recidivism to obesity. BW-changes including BW-loss and -regain is associated with marked alterations in energy expenditure (EE) and adipose tissue (AT) metabolism. Since these processes are sex-specifically controlled, we investigated sexual dimorphisms in metabolic processes during BW-dynamics (gain-loss-regain).Research DesignObesity was induced in C57BL/6J male (m) and female (f) mice by 15 weeks high-fat diet (HFD) feeding. Subsequently BW was reduced (-20%) by caloric restriction (CR) followed by adaptive feeding, and a regain-phase. Measurement of EE, body composition, blood/organ sampling were performed after each feeding period. Lipolysis was analyzed ex-vivo in gonadal AT.ResultsMale mice exhibited accelerated BW-gain compared to females (relative BW-gain m:140.5±3.2%; f:103.7±6.5%; p<0.001). In consonance, lean mass-specific EE was significantly higher in females compared to males during BW-gain. Under CR female mice reached their target-BW significantly faster than male mice (m:12.2 days; f:7.6 days; p<0.001) accompanied by a sustained sex-difference in EE. In addition, female mice predominantly downsized gonadal AT whereas the relation between gonadal and total body fat was not altered in males. Accordingly, only females exhibited an increased rate of forskolin-stimulated lipolysis in AT associated with significantly higher glycerol concentrations, lower RER-values, and increased AT expression of adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Analysis of AT lipolysis in estrogen receptor alpha (ERα)–deficient mice revealed a reduced lipolytic rate in the absence of ERα exclusively in females. Finally, re-feeding caused BW-regain faster in males than in females.ConclusionThe present study shows sex-specific dynamics during BW-gain-loss-regain. Female mice responded to CR with an increase in lipolytic activity, and augmented lipid-oxidation leading to more efficient weight loss. These processes likely involve ERα-dependent signaling in AT and sexual dimorphic regulation of genes involved in lipid metabolism.

LXRα fuels fatty acid-stimulated oxygen consumption in white adipocytes

“…Unlike previous studies ( 41, 71 ), we were not able to detect any increase in either serum FFA or glycerol levels in our male wild-type mice after T0901317 injections compared with saline controls. This difference may be due to the use of different genders in these experiments and the length of fasting prior to blood collection ( 41,42,71,72 ). Finally, studies in primary mouse adipocytes confi rmed our fi ndings in the animal models.…”

Conditional Knock-out Reveals a Requirement for O-Linked N-Acetylglucosaminase (O-GlcNAcase) in Metabolic Homeostasis

“…RER is a sensitive measure of metabolic rate and has been reported to be altered as the result of a number of loss of function mutations in the mouse (73)(74)(75). An increased basal metabolic rate and RER were observed in fat-specific insulin receptor knock-out mice (76).…”

Sex differences in sympathetic innervation and browning of white adipose tissue of mice

“…Indeed, crucial roles of female sex hormones in adipose tissue metabolism have been demonstrated [16, 17], and it has been shown that estrogen can directly activate lipolysis through estrogen receptor alpha signaling in adipocytes [17–19]. In addition to direct activation of lipolysis, sex hormones influence body fat distribution, and subcutaneous fat is more abundant in women [2].…”